ABSTRACT
PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.
Subject(s)
Abnormalities, Multiple , Eye Abnormalities , Kidney Diseases, Cystic , Humans , Cerebellum/diagnostic imaging , Cerebellum/pathology , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Eye Abnormalities/pathology , Retina/diagnostic imaging , Retina/pathology , Cytoskeletal ProteinsABSTRACT
Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimise quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne Muscular Dystrophy module of the Pediatric Quality of Life Inventory (PedsQLTMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQLTMDMD for paediatric patients with DMD, using French multicentre descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatment dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQLTMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.
Subject(s)
Muscular Dystrophy, Duchenne , Quality of Life , Child , Humans , Surveys and Questionnaires , Muscular Dystrophy, Duchenne/diagnosis , Cross-Sectional Studies , Goals , Psychometrics , Reproducibility of Results , ParentsABSTRACT
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.
Subject(s)
Muscle Development/physiology , Muscle, Skeletal/growth & development , Muscular Dystrophy, Duchenne/pathology , Myoblasts/cytology , Ryanodine Receptor Calcium Release Channel/metabolism , Calcium/metabolism , Calcium Signaling/physiology , Cell Differentiation/genetics , Cell Differentiation/physiology , Cells, Cultured , Child , Child, Preschool , Dystrophin/metabolism , Humans , Male , Muscle Development/genetics , Muscle Fibers, Skeletal/pathology , Muscular Dystrophy, Duchenne/metabolism , Ryanodine Receptor Calcium Release Channel/genetics , Sarcoplasmic Reticulum/metabolism , Tacrolimus Binding Proteins/metabolismABSTRACT
Calcium (Ca2+ ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca2+ entry, storage, and release. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling extracellular Ca2+ entry, and mainly relies on the accurate interplay between the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca2+ homeostasis and are associated with severe human disorders. Recessive loss-of-function mutations impair SOCE and cause combined immunodeficiency, while dominant gain-of-function mutations induce excessive extracellular Ca2+ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.
Subject(s)
Biomarkers , Blood Platelet Disorders/diagnosis , Blood Platelet Disorders/genetics , Dyslexia/diagnosis , Dyslexia/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Ichthyosis/diagnosis , Ichthyosis/genetics , Migraine Disorders/diagnosis , Migraine Disorders/genetics , Miosis/diagnosis , Miosis/genetics , Mutation , Myopathies, Structural, Congenital/diagnosis , Myopathies, Structural, Congenital/genetics , Spleen/abnormalities , Alleles , Calcium/metabolism , Disease Management , Erythrocytes, Abnormal , Gain of Function Mutation , Genetic Association Studies/methods , Genotype , Humans , Muscle Fatigue/genetics , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , ORAI1 Protein/genetics , ORAI1 Protein/metabolism , Phenotype , Protein Binding , Protein Interaction Domains and Motifs , Stromal Interaction Molecule 1/genetics , Stromal Interaction Molecule 1/metabolismABSTRACT
Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2-18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1-5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8-14), and patients used a wheelchair at a mean age of 16 years (14-18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.
Subject(s)
Cytoskeletal Proteins/genetics , Giant Axonal Neuropathy/genetics , Mutation , Adolescent , Brain/pathology , Child , Child, Preschool , Female , Giant Axonal Neuropathy/epidemiology , Giant Axonal Neuropathy/pathology , Giant Axonal Neuropathy/physiopathology , Humans , Male , Retrospective StudiesABSTRACT
N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.
Subject(s)
Epilepsy, Generalized/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Adult , Amino Acid Sequence/genetics , Animals , Child , Child, Preschool , Epilepsy, Generalized/physiopathology , Female , Gene Expression Regulation/genetics , Glutamic Acid/metabolism , HEK293 Cells , Humans , Male , Neurons/metabolism , Polymorphism, Single Nucleotide/genetics , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Transmission/geneticsABSTRACT
BACKGROUND: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of ß-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing. METHODS: Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients. RESULTS: Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before. CONCLUSION: Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.
Subject(s)
Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 4 , Genetic Association Studies , Genetic Predisposition to Disease , Muscular Dystrophy, Facioscapulohumeral/diagnosis , Muscular Dystrophy, Facioscapulohumeral/genetics , Telomere/genetics , Alleles , Chromosome Deletion , Genetic Association Studies/methods , Genetic Loci , Genotype , Humans , PedigreeABSTRACT
The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Subject(s)
Exotropia/genetics , Hypertension, Pulmonary/genetics , Intellectual Disability/genetics , Mental Retardation, X-Linked/genetics , Methyl-CpG-Binding Protein 2/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosomes, Human, X/genetics , Developmental Disabilities/complications , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Epilepsy/complications , Epilepsy/genetics , Epilepsy/physiopathology , Exotropia/complications , Exotropia/physiopathology , France/epidemiology , Humans , Hyperopia/complications , Hyperopia/genetics , Hyperopia/physiopathology , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/physiopathology , Infant , Intellectual Disability/complications , Intellectual Disability/physiopathology , Male , Mental Retardation, X-Linked/complications , Mental Retardation, X-Linked/physiopathology , Pedigree , Phenotype , Somatosensory Disorders/genetics , Somatosensory Disorders/physiopathology , Stereotypic Movement Disorder/complications , Stereotypic Movement Disorder/genetics , Stereotypic Movement Disorder/physiopathology , Young AdultABSTRACT
Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable-isotope-labeled substrate (D3-creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended. Together, these measures decreased, by a first order of magnitude, creatine concentrations in the incubation medium at the start of creatine-uptake studies and allowed to functionally discriminate between 4 hemizygous male and 4 heterozygous female patients with X-linked SLC6A8 deficiency, and between this cohort of eight patients and controls. The functional assay corroborated genetic diagnosis of SLC6A8 deficiency. Gene anomalies in our small cohort included splicing site (c.912Gâ¯>â¯A [p.Ile260_Gln304del], c.778-2Aâ¯>â¯G and c.1495â¯+â¯2â¯Tâ¯>â¯G), substitution (c.407Câ¯>â¯T) [p.Ala136Val] and deletion (c.635_636delAG [p.Glu212Valfs*84] and c.1324delC [p.Gln442Lysfs*21]) variants with reduced creatine transporter function validating their pathogenicity, including that of a previously unreported c.1324delC variant. The present assay adaptations provide an easy, reliable and discriminative manner for exploring creatine transporter activity and disease variations. It might apply to drug testing or other evaluations in the genetic and metabolic horizons covered by the emerging functions of creatine and its transporter, in a way, however, requiring and completed by additional studies on female patients and blood-brain barrier permeability properties of selected compounds. As a whole, the proposed assay of creatine transporter positively adds to currently existing measurements of this transporter activity, and determining on a large scale the extent of its exact suitability to detect female patients should condition in the future its transfer in clinical practice.
Subject(s)
Brain Diseases, Metabolic, Inborn/metabolism , Creatine/deficiency , Fibroblasts/metabolism , Mental Retardation, X-Linked/metabolism , Mutation , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Adolescent , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/pathology , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Creatine/genetics , Creatine/metabolism , Female , Fibroblasts/pathology , Follow-Up Studies , Humans , Infant , Male , Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/pathology , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/metabolism , PrognosisABSTRACT
Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
Subject(s)
Muscle Proteins/genetics , Myopathies, Structural, Congenital/genetics , Adult , Consanguinity , Exome , Female , Humans , Male , Mutation , Myopathies, Structural, Congenital/pathology , Myopathies, Structural, Congenital/physiopathology , PedigreeABSTRACT
High resolution oxymetry study (HROS) of skeletal muscle usually requires 90-120 min preparative phase (dissection, permeabilization and washing). This work reports on the suitability of a rapid muscle preparation which by-passes this long preparation. For a few seconds only, muscle biopsy from pigs is submitted to gentle homogenization at 8000 rotations per minute using an ultra-dispersor apparatus. Subsequent HROS is performed using FCCP instead of ADP, compounds crossing and not plasma membrane, respectively. This simplified procedure compares favorably with classical (permeabilized fibers) HROS in terms of respiratory chain complex activities. Mitochondria from cells undergoing ultradispersion were functionally preserved as attested by relative inefficacy of added cytochrome C (not crossing intact mitochondrial outer membrane) to stimulate mitochondrial respiration. Responsiveness of respiration to ADP (in the absence of FCCP) suggested that these intact mitochondria were outside cells disrupted by ultradispersion or within cells permeated by this procedure.
Subject(s)
Cell Respiration , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Oxygen Consumption , Animals , Biopsy , Electron Transport , Electron Transport Chain Complex Proteins/metabolism , Female , Mitochondrial Membranes/metabolism , Muscle Fibers, Skeletal/metabolism , Permeability , SwineABSTRACT
BACKGROUND: Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. METHODS: In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. FINDINGS: 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients). INTERPRETATION: Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. FUNDING: Santhera Pharmaceuticals.
Subject(s)
Antioxidants/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Respiration Disorders/drug therapy , Ubiquinone/analogs & derivatives , Adolescent , Child , Double-Blind Method , Humans , Male , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/physiopathology , Peak Expiratory Flow Rate , Respiration Disorders/etiology , Respiration Disorders/physiopathology , Respiratory Function Tests , Respiratory Muscles/physiopathology , Treatment Outcome , Ubiquinone/therapeutic useABSTRACT
Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.
Subject(s)
Brain Diseases/genetics , Chromosomes, Human, X/genetics , Gene Duplication , Magnetic Resonance Imaging/methods , Mental Retardation, X-Linked/genetics , Methyl-CpG-Binding Protein 2/genetics , Adolescent , Adult , Brain Diseases/pathology , Child , Child, Preschool , Female , Genetic Association Studies , Genotype , Humans , Infant , Infant, Newborn , Male , Mental Retardation, X-Linked/pathology , Middle Aged , Pedigree , Phenotype , Prognosis , Young AdultABSTRACT
The 15q13.3 heterozygous microdeletion is a fairly common microdeletion syndrome with marked clinical variability and incomplete penetrance. The average size of the deletion, which comprises six genes including CHRNA7, is 1.5 Mb. CHRNA7 has been identified as the gene responsible for the neurological phenotype in this microdeletion syndrome. Only seven patients with a homozygous microdeletion that includes at least CHRNA7, and is inherited from both parents have been described in the literature. The aim of this study was to further describe the distinctive eye manifestations from the analysis in the three French patients diagnosed with the classical 1.5 Mb homozygous microdeletion. Patients' ages ranged from 30 months to 9 years, and included one sib pair. They all displayed a remarkably severe identifiable clinical phenotype that included congenital blindness and convulsive encephalopathy with inconstant abnormal movements. The ophthalmological examination revealed a lack of eye tracking, optic nerve pallor, an immature response with increased latencies with no response to the checkerboard stimulations at the visual evoked potential examination, and a distinctive retina dystrophy with a negative electroretinogram in which the "b" wave was smaller than the "a" wave after a dark adapted pupil and bright flash in all patients. Clear genotype-phenotype correlations emerged, showing that this eye phenotype was secondary to homozygous deletion of TRPM1, the gene responsible for autosomal recessive congenital stationary night blindness. The main differential diagnosis is ceroid lipofuscinosis.
Subject(s)
Blindness/genetics , Chromosome Disorders/genetics , Intellectual Disability/genetics , Neuronal Ceroid-Lipofuscinoses/genetics , Seizures/genetics , TRPM Cation Channels/genetics , alpha7 Nicotinic Acetylcholine Receptor/genetics , Child , Child, Preschool , Chromosome Deletion , Chromosome Disorders/pathology , Chromosomes, Human, Pair 15/genetics , Electroretinography , Eye/pathology , Eye Abnormalities/genetics , Eye Diseases, Hereditary/genetics , Female , Genetic Association Studies , Genetic Diseases, X-Linked/genetics , Humans , Intellectual Disability/pathology , Male , Myopia/genetics , Neuronal Ceroid-Lipofuscinoses/pathology , Night Blindness/genetics , Optic Nerve/abnormalities , Retinal Dystrophies/genetics , Seizures/pathologyABSTRACT
Traditional measures of respiratory function in children with Duchenne muscular dystrophy (DMD) are based on maximal inspiratory pressure (PImax) and vital capacity (VC). Sniff nasal inspiratory pressure (SNIP) measurements are easily performed by young children with neuromuscular disorders. The clinical value of SNIP in the longitudinal assessment of respiratory weakness remains to be assessed. The objective of the present study was to assess longitudinally the changes in SNIP, PImax and VC with age in DMD children. We hypothesised that their longitudinal assessment would show an earlier decline in SNIP than VC. A 3-year, prospective follow-up, at 6-month intervals of, 33 steroid-naïve, 5-20-year-old DMD patients was analysed using a linear mixed model. SNIP measurements were reliable (within-session coefficient of variation 8%). SNIP and VC increased until 10.5 and 12.5 years of age, respectively, and declined thereafter, while PImax did not change with age. SNIP was an earlier marker of decline in respiratory muscle strength (at 10.5 years) than VC (at 12.5 years) in young DMD patients. SNIP longitudinal assessment is useful in the detection of inspiratory strength decline in young DMD patients when VC values remain within normal values and as an outcome measure in clinical trials for emerging therapeutics in young DMD patients from the age of 5 years.
Subject(s)
Inhalation , Muscle Weakness/diagnosis , Muscular Dystrophy, Duchenne/diagnosis , Pressure , Respiratory Muscles/physiopathology , Adolescent , Child , Child, Preschool , Follow-Up Studies , Humans , Linear Models , Muscle Weakness/etiology , Muscular Dystrophy, Duchenne/complications , Prospective Studies , Respiratory Function Tests/methods , Young AdultABSTRACT
Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.
Subject(s)
Creatine/metabolism , Glycine/analogs & derivatives , White People , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/metabolism , Case-Control Studies , Child , Child, Preschool , Creatine/blood , Creatine/urine , Female , France , Glycine/blood , Glycine/metabolism , Glycine/urine , Humans , Infant , Infant, Newborn , Male , Middle Aged , Reference Values , Sex Factors , Young AdultSubject(s)
Autoantibodies/metabolism , Autoimmune Diseases/diagnosis , Hydroxymethylglutaryl CoA Reductases/immunology , Muscular Diseases/diagnosis , Muscular Diseases/immunology , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Autoimmune Diseases/rehabilitation , Delayed Diagnosis , Diagnosis, Differential , Disease Progression , Female , Humans , Muscle, Skeletal/immunology , Muscle, Skeletal/pathology , Muscular Diseases/pathology , Muscular Diseases/rehabilitation , Young AdultABSTRACT
AIM: To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). METHOD: Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7-24y) were assessed using standardized instruments and cognitive testing of general intelligence, visual attention, and visual-spatial construction abilities. RESULTS: Nineteen patients had repeated a school grade. The mean (SD) Full-scale IQ was 73.6 (17.5) and mean Verbal IQ was significantly higher than the mean Performance IQ: 80.2 (19.22) versus 72.95 (15.58), p=0.01. Fifteen patients had one or more diagnoses on the DSM-IV axis 1, including internalizing disorders (phobia, n=7; mood disorder, n=6; other anxiety disorders, n=5) and attention-deficit-hyperactivity disorder, inattentive subtype (n=8). Twelve out of 22 patients had alexithymia (inability to express feelings with words and to recognize and share emotional states). Cognitive testing found severe impairments in visual attention and visual-spatial construction abilities in four out of 18, and 14 out of 24 patients respectively. No diagnosis was correlated with the transmitting parent's sex or with cytosine-thymine-guanine (CTG) repeat numbers. Patients with severe visual-spatial construction disabilities had a significantly longer CTG expansion size than those with normal visual-spatial abilities (p=0.04). INTERPRETATION: Children and adolescents with childhood DM1 have frequent diagnoses on DSM-IV axis 1, with internalizing disorders being the most common type of disorder. They also have borderline low intelligence and frequent impairments in attention and visual-spatial construction abilities.
Subject(s)
Cognition Disorders/diagnosis , Cognition Disorders/genetics , Mental Disorders/diagnosis , Mental Disorders/genetics , Myotonic Dystrophy/diagnosis , Myotonic Dystrophy/genetics , Phenotype , Adolescent , Attention , Child , Comorbidity , DNA Mutational Analysis , Female , Humans , Intelligence/genetics , Male , Pattern Recognition, Visual , Psychomotor Performance , Trinucleotide Repeat Expansion/genetics , Young AdultABSTRACT
The role of influenzalike illnesses and influenza vaccination in the development of Guillain-Barré syndrome (GBS), particularly the role of A/H1N1 epidemics and A/H1N1 vaccination, is debated. Data on all incident GBS cases meeting the Brighton Collaboration criteria that were diagnosed at 25 neurology centers in France were prospectively collected between March 2007 and June 2010, covering 3 influenzavirus seasons, including the 2009-2010 A/H1N1 outbreak. A total of 457 general practitioners provided a registry of patients from which 1,080 controls were matched by age, gender, index date (calendar month), and region to 145 cases. Causal relations were assessed by multivariate case-control analysis with adjustment for risk factors (personal and family history of autoimmune disorders, among others), while matching on age, gender, and calendar time. Influenza (seasonal or A/H1N1) or influenzalike symptoms in the 2 months preceding the index date was associated with GBS, with a matched odds ratio of 2.3 (95% confidence interval (CI): 0.7, 8.2). The difference in the rates of GBS occurring between influenza virus circulation periods and noncirculation periods was highly statistically significant (P = 0.004). Adjusted odds ratios for GBS occurrence within 6 weeks after seasonal and A/H1N1 vaccination were 1.3 (95% CI: 0.4, 4.1) and 0.9 (95% CI: 0.1, 7.6), respectively. Study results confirm that influenza virus is a likely risk factor for GBS. Conversely, no new concerns have arisen regarding influenza vaccination.